Stereoselective synthesis of enantiomerically pure, orthogonally protected 2-methylenecyclohexane-1,3,5-triols and 2,4,6-trihydroxycyclohexanones

Article abstract of DOI:10.1055/s-2003-41025

The triply silyl protected 2-methylenecyclohexane-1,3,5-triols 1a-c (C-1: tert-butyldimethylsilyl, TBDMS; C-3: trimethylsilyl, TMS; C-5: tert-butyldiphenylsilyl, TBDPS) were prepared from (R)-(-)-carvone in seven synthetic steps (overall yields: 29-53%). Ozonolysis in the presence of triethylamine yielded the triply protected 2,4,6-trihydroxycyclohexanones 2a-c (85%-quant.). The configuration of the products was proven by NOESY studies and by chemical correlation.

Full text of DOI:10.1055/s-2003-41025

PAPER
1827
Stereoselective Synthesis of Enantiomerically Pure, Orthogonally Protected
2-Methylenecyclohexane-1,3,5-triols and 2,4,6-Trihydroxycyclohexanones
C
yclohexane-1
t
,3,5-tr
e
iols fan Kirsch, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315.; E-mail: thorsten.bach@ch.tum.de
Received 4 July 2003
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday.
fore aimed at the preparation of compounds 1a–c and 2a–
Abstract: The triply silyl protected 2-methylenecyclohexane-
1,3,5-triols 1a–c (C-1: tert-butyldimethylsilyl, TBDMS; C-3: tri-
methylsilyl, TMS; C-5: tert-butyldiphenylsilyl, TBDPS) were pre-
pared from (R)-(–)-carvone in seven synthetic steps (overall yields:
29–53%). Ozonolysis in the presence of triethylamine yielded the
triply protected 2,4,6-trihydroxycyclohexanones 2a–c (85%–
quant.). The configuration of the products was proven by NOESY
studies and by chemical correlation.
c (Figure 1). The fourth possible diastereoisomer corre-
sponds to the enantiomer of 1b/2b with TBDMS and TMS
being exchanged. Its synthesis was not attempted.
Carvone, which is available in either enantiomerically
pure form was identified as ideal starting material for the
projected syntheses. Indeed, there is precedence for the
synthesis of a protected 2-methylenecyclohexane-1,3,5-
triol related to 1c from carvone.1,2a Other precedence for
some key steps relevant to our synthesis also exists and
the reference will be cited where appropriate. Despite the
precedence there have not been any reports on a fully si-
lyl-protected derivative of either 2-methylenecyclohex-
ane-1,3,5-triol or 2,4,6-trihydroxycyclohexanone nor has
there been a report which describes comprehensively the
synthesis of a suitably protected diastereoisomer related
to 2a and 2b. We feel that compounds 1 and 2 are ex-
tremely useful to synthetic organic chemists and we con-
sequently provide the details of our investigations in this
account. The method we established allows for the syn-
thesis of the title compounds 1 and 2 from (R)-(–)-carvone
(3) in a short and perfectly stereoselective way. The con-
figuration was proven by spectroscopic means and by
chemical correlation. Conversely, the enantiomers ent-1
and ent-2 are accessible from (S)-(+)-carvone.
In analogy to the seminal work by Tagano et al.2a and by
Yamamura et al.7 our synthetic plan was to first establish
the three stereogenic centers of 1 and 2 in carvone-derived
epoxy-alcohols. Subsequently, the iso-propenyl group
was to be transformed oxidatively into a hydroxy group
and the epoxide ring was to be opened by elimination.
Following this consideration (R)-(–)-carvone (3) was con-
verted to the known allylic alcohol 48 by Luche reduction
and oxidized to the known epoxide 59 (Scheme 1).
Key words: alcohols, carbocycles, oxidations, protecting groups,
stereoselective synthesis
Due to their inherent symmetry the parent 2-methylenecy-
clohexane-1,3,5-triol and 2,4,6-trihydroxycyclohexanone
occur in only three diastereomeric forms. Two diastereo-
isomers are achiral meso-compounds and one diastereo-
isomer is chiral. If appropriately protected, the same triols
occur in four diastereoisomeric forms all of which are
chiral. Some of these compounds have been previously
used as enantiomerically pure building blocks in organic
synthesis. Notable applications include the preparation of
carbocyclic nucleosides1 and Vitamin D analogues.2–4 We
became interested in the title compounds in connection
with our efforts to synthesize Wailupemycins B5 and A.6
We considered an orthogonal silyl protection ideal, to se-
quentially address the different hydroxy groups and there-
OTMS
OTMS
X
X
TBDPSO
OTBDMS
1a X = CH2
TBDPSO
OTBDMS
1b X = CH2
2b X = O
2a X = O
OTMS
X
O
H2O2, NaOH
(MeOH)
NaBH4, CeCl3
(MeOH)
O
TBDPSO
OTBDMS
3
quant.
75%
(R)-(−)-Carvone (3)
OH
O
1c X = CH2
2c X = O
5
4
Figure
1
The structure of the title compounds
1 and 2
Scheme 1 Diastereoselective introduction of new stereogenic
centers in (R)-(–)-carvone by reduction or epoxidation.
(TBDMS = tert-butyldimethylsilyl,
silyl, TMS = trimethylsilyl) and (R)-(–)-carvone (3).
TBDPS = tert-butyldiphenyl-
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1827,1836,ftx,en;Z09803SS.pdf.
DOI: 10.1055/s-2003-41025
© Georg Thieme Verlag Stuttgart · New York

1828
S. Kirsch, T. Bach
PAPER
Directed stereoselective oxidation of the allylic alcohol 4 ported
methylmagnesium
N-cyclohexyl-N-iso-
was achieved with MCPBA10 and the resulting epoxy-al- propylamide14 was less successful. In the transformation
cohol 6a was protected as its TBDMS ether (7a). The re- 9b
10b the yield was only 28% as compared to the
duction of compound 5 was conducted previously with a quantitative yield obtained with DAHPA. Facile TMS
variety of reducing agents.2,11 Luche reduction was most protection of the corresponding alcohols 10 yielded the ti-
useful for the stereoselective formation of compound 6b tle compounds 1 which can be further converted into the
whereas the reduction with L-Selectride gave the epimeric cyclohexanones 2 by ozonolysis and reductive work-up.
product 6c.2 TBDMS protection of the alcohols to the cor- The use of triethylamine (1% v/v relative to the solvent)
responding silyl ethers 7b and 7c concluded the sequence in the ozonolysis procedure was mandatory to avoid
of reactions as depicted in Scheme 2.
deprotection of the TMS ether. For the reductive work-up,
Me2S is superior to PPh3, as OPPh3 could not be separated
from the products in the latter case. An alternative oxida-
tive cleavage protocol employing the Lemieux–Johnson
protocol15 (OsO4/NaIO4) did not work and the starting
material was recovered unchanged. Attempted ozonolysis
of the free alcohol 10b led to an epimerization and yielded
a mixture of the desired cyclohexanone and its all-cis-
epimer. Compound 10b can also be protected at the free
hydroxy position with a MEM group (MEMCl, i-Pr2NEt,
CH2Cl2; 76% yield) or a pivaloyl group (t-BuCOCl,
DMAP, pyridine, CH2Cl2; 80% yield).
O
MCPBA
(CH2Cl2)
OH
OR
81%
4
6a : R = H
TBDMSCl, im (DMF)
91%
7a : R = TBDMS
O
NaBH4, CeCl3
(MeOH)
O
O
quant.
OR
5
6b : R = H
1. O3 (MeOH/CH2Cl2)
Al N
TBDMSCl, im (DMF)
94%
2. Ac2O, Et3N, DMAP
7b : R = TBDMS
O
3. K2CO3, MeOH
68%
(benzene)
89%
7a
O
RO
OTBDMS
L-Selectride
(THF)
8a: R = H
9a: R = TBDPS
TBDPSCl, im (DMF)
88%
OR
85%
6c : R = H
TBDMSCl, im (DMF)
94%
1. O3, NEt3 (1% v/v)
(MeOH/CH2Cl2)
2. Me2S
7c : R = TBDMS
OTMS
O
OR
Scheme 2 Synthesis of the three TBDMS-protected epoxy-alcohols
7 which already contain all three stereogenic centers present in the tar-
get compounds 1 and 2.
85%
TBDPSO
OTBDMS
TBDPSO
OTBDMS
2a
10a: R = H
TMSCl, im (DMF)
quant.
The oxidative cleavage of the 2-propenyl group was con-
ducted according to the Schreiber protocol.12 The Criegee
rearrangement is known to occur with retention of config-
uration. Compound 8c has been previously synthesized
from 7c in the very same fashion by Takano et al.2a The
protocol was successfully applied to the other diastero-
isomers 7a and 7b. Protection with the robust TBDPS
group was easily accomplished and gave the silyl ethers 9
(Scheme 3). The benzylation of the intermediate alcohol
8b was not possible with BnBr/NaH due to competitive
nucleophilic substitution at the epoxide ring whereas the
benzylation of alcohol 8c proceeded smoothly. A
methoxyethoxymethyl (MEM) protection of alcohol 8b
was facile but the corresponding MEM ether was unstable
in the subsequent elimination step. For the elimination ep-
oxide 9 allylic alcohol 10, we found the use of diethyl-
aluminium N-cyclohexyl-N-iso-propylamide (DAHPA)
sufficient to guarantee high conversions and excellent
yields. The corresponding amine is far less expensive than
2,2,6,6-tetramethylpiperidine which has been commonly
employed as the corresponding diethylaluminium tetram-
ethylpiperidide (DATMP).13 The use of the previously re-
1a: R = TMS
Compound
Yield [%]
10b/10c
99/98
1b/1c
90/73
2b/2c
8b/8c
9b/9c
quant./95
68/58
94/quant.
Scheme 3 Conversion of epoxy-alcohol 7a into the title compounds
1a and 2a. In an analogous fashion the alcohols 7b/7c gave the pro-
ducts 1b/1c and 2b/2c. Yields for this sequence are given on the bot-
tom of the scheme.
The relative configuration of product 2b could be easily
assigned based on its NOESY data (Figure 2).
The preparation of compounds 1c and 2c followed litera-
ture precedence and we therefore rely on the previous
configuration assignment for closely related products.1a,2
The only question to be addressed was consequently the
configuration assignment of compounds 1a and 2a. Due
to strong signal overlap, NOESY studies were not conclu-
sive. We conducted a chemical correlation, which relies
on the relative configuration of compound 11. The rela-
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

PAPER
Cyclohexane-1,3,5-triols
1829
2b
2a
quant. (d.r. = 9/1)
75% (d.r. = 3/1)
MgBr
(THF)
TMSO
OR
TMSO
OR
TBDPSO
OTBDMS
TBDPSO
OTBDMS
MEMCl, i Pr2NEt
12b: R = H
12a: R = H
(DCE)
79%
80%
13b: R = MEM
13a: R = MEM
Figure 2 Major NOESY contacts which prove the relative configu-
ration of compounds 2b and 11.
95%
quant.
K2CO3
(MeOH)
tive configuration of 11 was in turn easily deduced from
NOESY studies (Figure 2).
HO
HO
OMEM
OMEM
Addition of allylmagnesium bromide to ketone 2a yielded
as major product alcohol 12a, which was protected as its
MEM ether 13a. The MEM protection required high con-
centrations and high temperature in dichloroethane (DCE)
as the solvent.16 Subsequent TMS deprotection proceeded
best with potassium carbonate in MeOH and gave alcohol
14a which was further oxidized with 2-iodoxybenzoic
acid (IBX)17,18 to ketone 11. The same ketone was ob-
tained from the epimeric starting material 2b the relative
configuration of which was known. The stereogenic cen-
ters at the two carbon atoms to which the bulky silyloxy
(TBDMSO, TBDPSO) groups are attached remain un-
changed in the synthetic sequence and have to be identical
in 2a and 2b. Consequently, 2a and 2b must differ in the
configuration at the carbon atom to which the TMSO
group is attached.
TBDPSO
OTBDMS
TBDPSO
OTBDMS
14a
88%
14b
IBX
(DMSO)
98%
O
OMEM
TBDPSO
OTBDMS
11
Scheme 4 Synthesis of the allylated cyclohexanone 11 starting from
compounds 2a and 2b.
reactions the Grignard reagent approaches in an equatorial
fashion to a presumable cyclohexanone chair. We do not
have a conclusive explanation for the stereochemical out-
come of these reactions at present. For our synthetic route
to Wailupemycin B5 this result let us use compound 2b as
the starting material.
A notable result, which was obtained in the course of the
synthetic sequence depicted in Scheme 4 concerns the fa-
cial diastereoselectivity of the nucleophilic carbonyl at-
tack by the Grignard reagent. Contraintuitively, the all
equatorial cyclohexanone 2a reacts with significantly
lower selectivity (dr 3:1) than cyclohexanone 2b (dr 9:1)
in which the TMSO group resides in an axial position.
Moreover, the latter reaction proceeded in higher yields.
A sufficient reaction velocity for the conversion 2b
12b was achieved at –20 °C whereas at –78 °C the addi-
tion to 2b proceeded slowly. The carbonyl addition to cy-
clohexanone 2a could be conducted at –78 °C. In both
In summary, we have achieved the synthesis of the ke-
tones 2a–c in eight synthetic steps and in an overall yield
of 29–53%. They are useful building blocks containing
protected 1,3-diol subunits, which can be utilized in fur-
ther reactions.
Table 1 1H and 13C NMR Data for Compounds 6a, 7a,b, 8a,b, 9a,b, 10a–c, 1a–c and 2a–c
Product 1H NMR (360 MHz, CDCl3); , J (Hz) 13C NMR (90.6 MHz, CDCl3);
6b
1.05–1.19 (m, 1 H), 1.31 (s, 3 H), 1.50–1.54 (m, 4 H), 1.78– 19.1 (q), 20.6 (q), 30.6 (t), 34,3 (d), 36.2 (t), 60.7 (s), 61.9 (d) 68.9
2.09 (m, 1 H + OH), 2.09–2.19 (m, 2 H), 3.08–3.36 (m, 1 H), (d), 109.4 (t), 148.2 (s)
3.77–3.82 (m, 1 H), 4.57–4.63 (m, 2 H)
7a
0.09 (s, 3 H), 0.10 (s, 3 H), 0.91 (s, 9 H), 1.36 (s, 3 H), 1.51– –4.7 (q), –4.0 (q), 18.1 (s), 19.7 (q), 20.0 (q), 25.9 (q), 29.2 (t), 33.8
1.59 (m, 2 H), 1.65–1.75 (m, 4 H), 1.90–2.05 (m, 2 H), 3.02
(virt. d, J = ca. 5.0, 1 H), 3.93 (dd, J = 9.1, 5.9, 1 H), 4.67–4.68
(m, 2 H)
(t), 41.1 (d), 60.1 (s), 60.9 (d), 73.3 (d), 109.6 (t), 148.1 (s)
7b
–0.03 (s, 3 H), 0.00 (s, 3 H), 0.80 (s, 9 H), 0.95–1.06 (m, 1 H), –5.3 (q), –4.6 (q), 17.8 (s), 19.8 (q), 20.4 (q), 25.6 (q), 30.8 (t), 34.2
1.20 (s, 3 H), 1.46–1.58 (m, 4 H), 1.66–1.72 (m, 1 H), 1.92– (d), 37.5 (t), 60.7 (s), 62.5 (d), 69.8 (d), 109.7 (t), 148.3 (s)
2.08 (m, 2 H), 2.98 (s, 1 H), 3.74 (dd, J = 10.2, 6.3, 1 H), 4.57–
4.58 (m, 2 H)
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

1830
S. Kirsch, T. Bach
PAPER
Table 1 1H and 13C NMR Data for Compounds 6a, 7a,b, 8a,b, 9a,b, 10a–c, 1a–c and 2a–c (continued)
Product 1H NMR (360 MHz, CDCl3); , J (Hz) 13C NMR (90.6 MHz, CDCl3);
8a
8b
9a
0.09 (s, 3 H), 0.11 (s, 3 H), 0.92 (s, 9 H), 1.35 (s, 3 H), 1.34–1.85 –4.7 (q), –4.2 (q), 18.1 (s), 19.7 (q), 25.8 (q), 33.3 (t), 38.1 (t), 58.6
(m, 3 H + OH), 2.20 (dt, J = 15.7, 5.7, 1 H), 2.98 (d, J = 4.5, 1 (d), 60.0 (s), 65.7 (d), 70.7 (d)
H), 3.62–3.73 (m, 1 H), 4.01 (dd, J = 9.1, 5.5, 1 H)
0.04 (s, 3 H), 0.06 (s, 3 H), 0.82 (s, 9 H), 1.27 (s, 3 H), 1.61– –5.3 (q), –4.8 (q), 17.6 (s), 19.9 (q), 25.5 (q), 33.5 (t), 33.7 (t), 58.1
1.72 (m, 2 H), 1.82–2.10 (m, 2 H), 2.96 (br s, 1 H), 3.72 (br s, (s), 58.9 (d), 63.0 (d), 70.2 (d)
1 H), 4.06–4.12 (m, 1 H + OH)
–0.08 (s, 3 H), –0.04 (s, 3 H), 0.86 (s, 9 H), 1.04 (s, 9 H), 1.23 –4.9 (q), –4.3 (q), 18.0 (s), 19.0 (s), 19.1 (q), 25.8 (q), 26.9 (q), 33.7
(s, 3 H), 1.55–1.65 (m, 2 H), 1.87 (dd, J = 14.9, 10.0, 1 H),
(t), 38.1 (t), 58.2 (d), 60.1 (s), 67.1 (d), 71.0 (d), 127.5 (d), 127.6 (d),
2.02–2.06 (m, 1 H), 2.78 (d, J = 5.3, 1 H), 3.52–3.64 (m, 2 H), 129.6 (d), 129.7 (d), 134.2 (s), 134.3 (s), 135.7 (d), 135.7 (d)
7.34–7.44 (m, 6 H), 7.66–7.70 (m, 4 H)
9b
–0.11 (s, 3 H), –0.05 (s, 3 H), 0.83 (s, 9 H), 1.03 (s, 9 H), 1.20– –5.2 (q), –4.6 (q), 17.9 (s), 19.1 (s), 19.4 (q), 25.7 (q), 26.9 (q), 35.1
1.34 (m, 4 H), 1.71–1.84 (m, 2 H), 2.33 (dt, J = 14.5, 2.6, 1 H), (t), 42.3 (t), 60.8 (s), 62.7 (d), 64.8 (d), 69.3 (d), 127.5 (d), 127.6 (d),
2.99 (br s, 1 H), 3.55 (dd, J = 10.4, 6.3, 1 H), 3.74–3.79 (m, 1 129.6 (d), 129.6 (d), 134.2 (s), 134.3 (s), 135.6 (d), 135.7 (d)
H), 7.31–7.43 (m, 6 H), 7.66–7.71 (m, 4 H)
10a
10b
10c
–0.07 (s, 3 H), –0.05 (s, 3 H), 0.85 (s, 9 H), 1.06 (s, 9 H), 1.40– –5.2 (q), –5.1 (q), 18.3 (s), 19.1 (s), 25.8 (q), 26.9 (q), 45.6 (t), 45.9
1.56 (m, 2 H + OH), 1.96–2.00 (m, 1 H), 2.29–2.33 (m, 1 H), (t), 66.3 (d), 67.9 (d), 68.4 (d), 102.2 (t), 127.6 (d), 127.6 (d), 129.6
3.69–3.85 (m, 3 H), 5.01 (d, J = 1.6, 1 H), 5.14 (d, J = 1.6, 1 (d), 129.7 (d), 134.1 (s), 134.2 (s), 135.7 (d), 135.8 (d), 152.9 (s)
H), 7.35–7.45 (m, 6 H), 7.60–7.72 (m, 4 H)
–0.06 (s, 3 H), –0.04 (s, 3 H), 0.86 (s, 9 H), 1.07 (s, 9 H), 1.23 –5.2 (q), –4.9 (q), 18.3 (s), 19.1 (s), 25.8 (q), 26.9 (q), 42.6 (t), 46.3
(br s, 1 H, OH), 1.37–1.61 (m, 2 H), 2.03–2.17 (m, 2 H), 4.20– (t), 66.3 (d), 67.2 (d), 72.7 (d), 108.7 (t), 127.7 (d), 127.9 (d), 129.5
4.28 (m, 2 H), 4.41–4.43 (m, 1 H), 4.90–4.91 (m, 1 H), 5.08– (d), 129.6 (d), 134.4 (s), 134.5 (s), 135.7 (d), 135.8 (d), 151.3 (s)
5.09 (m, 1 H), 7.33–7.45 (m, 6 H), 7.60–7.74 (m, 4 H)
–0.01 (s, 3 H), 0.04 (s, 3 H), 0.85 (s, 9 H), 1.07 (s, 9 H), 1.43– –5.0 (q), –5.0 (q), 18.1 (s), 19.2 (s), 25.8, 26.9 (q), 43.8 (t), 44.1 (t),
1.59 (m, 2 H), 1.82–1.88 (m, 1 H), 1.96–2.03 (m, 2 H), 2.03
66.3 (d), 69.4 (d), 70.1 (d), 104.6 (t), 127.6 (d), 127.6 (d), 129.7 (d),
(s, 1 H, OH), 4.30–4.31 (m, 1 H), 4.49–4.55 (m, 2 H), 5.00 (d, 129.7 (d), 133.9 (s), 134.0 (s), 134.8 (d), 135.7 (d), 152.4 (s)
J = 1.4, 1 H), 5.06 (d, J = 1.4, 1 H), 7.34–7.43 (m, 6 H), 7.63–
7.74 (m, 4 H)
1a
1b
1c
2a
2b
–0.05 (s, 3 H), –0.03 (s, 3 H), 0.03 (s, 9 H), 0.86 (s, 9 H), 1.06 –5.5 (q), –5.4 (q), –0.6 (q), 18.0 (s), 18.7 (s), 25.5 (q), 26.5 (q), 45.7
(s, 9 H), 1.41–1.51 (m, 2 H), 2.02–2.03 (m, 2 H), 3.70–3.79
(m, 3 H), 5.03–5.07 (m, 2 H), 7.35–7.43 (m, 6 H), 7.66–7.69 (d), 129.3 (d), 129.3 (d), 133.9 (s), 133.9 (s), 135.4 (d), 135.4 (d),
(m, 4 H) 151.6 (s)
(t), 45.8 (t), 66.2 (d), 67.7 (d), 68.1 (d), 102.7 (t), 127.3 (d), 127.3
–0.04–0.05 (m, 15 H), 0.85 (s, 9 H), 1.05 (s, 9 H), 1.39–1.49 –5.1 (q), –4.9 (q), –0.0 (q), 18.3 (s), 19.1 (s), 25.9 (q), 26.9 (q), 44.3
(m, 2 H), 1.90–1.95 (m, 1 H), 2.05–2.09 (m, 1 H), 4.17–4.32 (t), 46.3 (t), 66.6 (d), 67.5 (d), 72.7 (d), 106.8 (t), 127.4 (d), 127.5
(m, 3 H), 4.78 (virt. t, J = ca. 2.0, 1 H), 4.98 (virt. t, J = ca. 2.0, (d), 129.5 (d), 129.6 (d), 134.6 (s), 134.7 (s), 135.8 (d), 135.8 (d),
1 H), 7.33–7.40 (m, 6 H), 7.65–7.69 (m, 4 H)
151.9 (s)
0.05 (s, 3 H), 0.08 (s, 3 H), 0.12 (s, 9 H), 0.85 (s, 9 H), 1.07 (s, –5.0 (q), –4.9 (q), –0.1 (q), 18.4 (s), 19.2 (s), 25.9 (q), 27.0 (q), 44.2
9 H), 1.25–1.34 (m, 2 H), 1.91–2.03 (m, 2 H), 4.19 (br s, 1 H), (t), 44.2 (t), 67.6 (d), 67.9 (d), 68.3(d), 102.3 (t), 127.7 (d), 127.7
4.54–4.61 (m, 2 H), 5.05–5.08 (m, 2 H), 7.35–7.44 (m, 6 H), (d), 129.8 (d), 129.8 (d), 133.9 (s), 133.9 (s), 135.7 (d), 135.7 (d),
7.64–7.69 (m, 4 H)
153.9 (s)
–0.09 (s, 3 H), –0.04 (s, 12 H), 0.83 (s, 9 H), 1.06 (s, 9 H),
1.80–1.93 (m, 2 H), 2.19–2.32 (m, 2 H), 3.94 (dd, J = 12.3,
5.9, 2 H), 4.09 (tt, J = 11.1, 4.3, 1 H), 7.37–7.44 (m, 6 H),
7.61–7.73 (m, 4 H)
–5.4 (q), –4.7 (q), –0.0 (q), 18.5 (s), 19.1 (s), 25.8 (q), 26.8 (q), 44.9
(t), 45.0 (t), 65.3 (d), 71.2 (d), 71.7 (d), 127.7 (d), 127.7 (d), 129.9
(d), 129.9 (d), 133.8 (s), 133.8 (s), 135.7 (d), 135.7 (d), 206.1 (s, C1)
–0.04 (s, 9 H), –0.03 (s, 3 H), 0.03 (s, 3 H), 0.84 (s, 9 H), 1.05 –5.4 (q), –4.8 (q), –0.3 (q), 18.4 (s), 19.1 (s), 25.8 (q), 26.9 (q), 43.5
(s, 9 H), 1.72 (ddd, J = 13.7, 10.5, 2.9, 1 H), 1.74–1.85 (m, 1 (t), 44.9 (t), 65.3 (d), 70.4 (d), 73.4 (d), 127.6 (d), 127.6 (d), 129.7
H), 2.02 (ddd, J = 13.7, 7.5, 4.1, 1 H), 2.15–2.26 (m, 1 H),
4.00 (virt. t, J = ca. 2.9, 1 H), 4.38–4.47 (m, 1 H), 4.52 (dd,
J = 12.0, 6.4, 1 H), 7.34–7.46 (m, 6 H), 7.61–7.74 (m, 4 H)
(d), 129.7 (d), 133.9 (s), 134.0 (s), 135.7 (d), 135.7 (d), 208.0 (s)
2c
0.03 (s, 3 H), 0.13 (s, 3 H), 0.14 (s, 9 H), 0.89 (s, 9 H), 1.11 (s, –5.1 (q), –4.2 (q), 0.4 (q), 18.9 (s), 19.6 (s), 26.2 (q), 27.3 (q), 44.3
9 H), 1.65 (br t, J = 13.4, 2 H), 2.17–2.24 (m, 2 H), 4.23 (br s, (t), 44.4 (t), 66.8 (d), 72.0 (d), 72.7 (d), 128.3 (d), 128.3 (d), 130.4
1 H), 4.74–4.82 (m, 2 H), 7.36–7.44 (m, 6 H), 7.64–7.73 (m, (d), 130.5 (d), 133.7 (s), 133.8 (s), 136.0 (d), 207.5 (s)
4 H)
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

PAPER
Cyclohexane-1,3,5-triols
1831
All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under Ar. THF was
distilled from sodium immediately prior to use. N,N-Di-iso-propyl-
ethylamine was distilled from calcium hydride. All other chemicals
were either commercially available or prepared according to the cit-
ed references. Ozonolyses were conducted using a Fischer Ozone
Generator 502. TLC: Merck glass sheets (0.25 mm silica gel 60,
mmol) in DMF (30 mL) was stirred at 20 °C for 24 h. Et2O (300
mL) was added and the solution was washed with H2O (400 mL).
The aqueous layer was extracted with Et2O (2 × 150 mL). The com-
bined organic phases were washed with H2O (250 mL) and brine
(300 mL), dried (Na2SO4), filtered, and the solvent was evaporated.
Flash chromatography (P–EtOAc, 95:5) gave 12.5 g (44.2 mmol,
94%) of the protected alcohol 7b as a colorless oil; Rf 0.80 (P–
20
F
254), eluent given in brackets. Detection by UV or coloration with
EtOAc, 80:20); [ ]D –38.9 (c 1.95, CHCl3).
cerium ammonium molybdate (CAM). Optical Rotation: Perkin-
Elmer 241 MC. NMR: Bruker AV-360, AV-500. 1H and 13C NMR
spectra were recorded in CDCl3 at ambient temperature unless stat-
ed otherwise. Chemical shifts are reported relative to tetramethylsi-
lane as internal standard. Apparent multiplets, which occur as a
result of the accidental equality of coupling constants of magneti-
cally non-equivalent protons are marked as virtual (virt.). The mul-
tiplicities of the 13C NMR signals were determined by DEPT
experiments. IR: Perkin-Elmer 1600 FT-IR. MS: Finnigan MAT
8200 (EI). Elemental Analysis: Elementar Vario EL. Flash chroma-
tography was performed on silica gel 60 (Merck, 230-400 mesh)
(ca. 50 g for 1 g of material to be separated) with the indicated elu-
ent. Common solvents for chromatography [pentane (P), EtOAc]
were distilled prior to use.
IR (neat): 3081 (m), 2928, 2855 (vs), 1645 (s), 1472 (s), 1373 (s),
1360 (s), 1254 (vs), 1095 (vs), 1046 (s), 1005 (m), 892 (vs), 837
cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 225 (74) [M+ – t-Bu], 155 (14), 129 (32),
75 (100), 43 (12).
Anal. Calcd for C16H30O2Si (282.202): C, 68.03; H, 10.70. Found:
C, 67.94; H, 10.61.
(1S,3R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-6-methyl-7-oxabi-
cyclo[4.1.0]heptan-3-ol (8a)
To a solution of 7a (1.83 g, 6.5 mmol) in CH2Cl2 (20 mL) was added
MeOH (4 mL). The reaction mixture was ozonized at –78 °C until
a pale blue color appeared. Nitrogen was bubbled through the mix-
ture until the mixture became colorless. After warming to r.t., Ac2O
(9.5 mL, 10.2 g, 100 mmol), Et3N (14.0 mL, 10.1 g, 100 mmol) and
a catalytic amount of DMAP (20 mg) was added. The reaction mix-
ture was then refluxed overnight (12 h), cooled to r.t. and poured
into sat. aq NH4Cl solution (80 mL). The aqueous layer was extract-
ed with CH2Cl2 (2 × 80 mL), and the combined organic layers were
washed with sat. aq NaHCO3 solution (150 mL) and brine (150
mL), dried over MgSO4, filtered and concentrated. The crude prod-
uct was dissolved in MeOH (50 mL) and treated with K2CO3 (0.5 g,
3.7 mmol). The mixture was stirred for 3 h at r.t., filtered and con-
centrated. The resultant liquid was then dissolved in CH2Cl2 (80
mL), washed with H2O (50 mL) and brine (50 mL) and subsequent-
ly dried (MgSO4). After filtration, the solvent was evaporated in
vacuo and the residue was purified by flash chromatography (P–
EtOAc, 70:30) to yield alcohol 8a as a colorless oil (1.14 g, 4.4
(1S,2R,4S,6R)-4-iso-Propenyl-1-methyl-7-oxabicyclo[4.1.0]hep-
tan-2-ol (6b)
CeCl3·7H2O (12 mmol, 2.23 g) was added to a solution of ketone 51a
(1.00 g, 6 mmol) in MeOH (15 mL). The mixture was stirred and
cooled to –20 °C. NaBH4 (6 mmol, 226 mg) was added in two por-
tions. After stirring for 15 min, H2O (100 mL) and Et2O (150 mL)
were added, the layers were separated, and the aqueous layer was
extracted with Et2O (2 × 50 mL). The combined organic layers were
washed with brine (200 mL), dried (Na2SO4), filtered, and concen-
trated. Flash chromatography (P–EtOAc, 80:20) gave alcohol 6b
(1.00 g, 5.99 mmol, quant.) in diastereomerically pure form; Rf 0.28
(P–EtOAc, 80:20); [ ]D20 –34.9 (c 1.23, CH2Cl2).
IR (neat): 3426 (vs, br), 3079 (m), 2968, 2931 (s), 1644 (m), 1447
(s), 1374 (s), 1289 (m), 1234 (m), 1169 (m), 1123 (m), 1037 (vs),
889 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 153 (9) [M+ – CH3], 150 (11) [M+ –
H2O], 135 (18), 121 (29), 107 (28), 95 (26), 87 (100), 81 (20), 74
(36), 67 (28), 43 (59).
20
mmol, 68%); Rf 0.12 (P–EtOAc, 80:20); [ ]D –26.1 (c 0.45,
CHCl3).
IR (neat): 3422 (vs, br), 2930, 2857 (vs), 1472 (s), 1362 (s), 1255
(vs), 1068 (vs), 1039 (vs), 1007 (vs), 892 (s), 836 (vs), 775 cm–1
(vs).
MS (EI, 70 eV): m/z (%) = 258 (1) [M+], 201 (10) [M+ – t-Bu], 183
(88), 157 (30), 75 (100).
tert-Butyl-[(1R,2R,4R,6S)-4-iso-propenyl-1-methyl-7-oxabicy-
clo[4.1.0]hept-2-yloxy]dimethylsilane (7a)
A solution of 6a4 (1.23 g, 7.3 mmol), TBDMSCl (3.0 mL, 8.76
mmol; 2.9 M solution in toluene), and imidazole (744 mg, 10.9
mmol) in DMF (12 mL) was stirred at 20 °C for 4 h. Et2O (100 mL)
was added and the solution was washed with H2O (150 mL). The
aqueous layer was extracted with Et2O (2 × 50 mL). The combined
organic layers were washed with H2O (150 mL) and brine (150 mL),
dried (Na2SO4), filtered, and the solvent was evaporated. Flash
chromatography (P–EtOAc, 95:5) gave 1.85 g (6.6 mmol, 91%) of
Anal. Calcd for C13H26O3Si (258.165): C, 60.42; H, 10.14. Found:
C, 60.09; H, 10.06.
(1R,3R,5R,6S)-5-(tert-Butyldimethylsilyloxy)-6-methyl-7-oxabi-
cyclo[4.1.0]heptan-3-ol (8b)
To a solution of 7b (6.2 g, 22.0 mmol) in CH2Cl2 (150 mL) was add-
ed MeOH (30 mL) and NaHCO3 (5.88 g, 70 mmol). The reaction
mixture was ozonized at –78 °C until a pale blue color appeared. Ni-
trogen was bubbled through the mixture until it became colorless.
After warming to r.t., Ac2O (33.1 mL, 35.7 g, 350 mmol), Et3N
(28.1 mL, 20.2 g, 200 mmol) and a catalytic amount of DMAP (50
mg) was added. The reaction mixture was then refluxed overnight
(12 h), cooled to r.t. and poured into sat. aq NH4Cl solution (300
mL). The aqueous layer was extracted with CH2Cl2 (2 × 250 mL),
and the combined organic layers were washed with sat. aq NaHCO3
solution (300 mL) and brine (300 mL), dried over MgSO4, filtered
and concentrated. The crude product was dissolved in MeOH (60
mL) and treated with K2CO3 (4.8 g, 36 mmol). The mixture was
stirred for 2 h at r.t., filtered and concentrated. The resultant liquid
was then dissolved in CH2Cl2 (300 mL), washed with H2O (200 mL)
and brine (200 mL) and subsequently dried (MgSO4). After filtra-
tion, the solvent was evaporated in vacuo and the residue was puri-
20
a colorless oil; Rf 0.37 (P–EtOAc, 95:5); [ ]D –33.5 (c 1.04,
CHCl3).
IR (neat): 3081 (m), 2927, 2856 (vs), 1643 (m), 1472 (s), 1373 (s),
1360 (s), 1254 (vs), 1094 (s), 1046 cm–1 (s).
MS (EI, 70 eV): m/z (%) = 282 (0.1) [M+], 225 (43) [M+ – t-Bu],
157 (28), 143 (68), 133 (100), 119 (65), 75 (98), 59 (28).
Anal. Calcd for C16H30O2Si (282.202): C, 68.03; H, 10.70. Found:
C, 67.85; H, 10.60.
tert-Butyl-[(1S,2R,4R,6R)-4-iso-propenyl-1-methyl-7-oxabicy-
clo[4.1.0]hept-2-yloxy]dimethylsilane (7b)
A solution of 6b (7.91 g, 47.1 mmol), TBDMSCl (19.5 mL, 56.5
mmol; 2.9 M solution in toluene), and imidazole (744 mg, 10.9
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

1832
S. Kirsch, T. Bach
PAPER
fied by flash chromatography (P–EtOAc, 80:20) to yield alcohol 8b
BuLi in hexane (2.5 M; 5.2 mL, 13 mmol) was added dropwise. The
resulting mixture was stirred at 0 °C for 10 min, a solution of
Et2AlCl (1.8 M in toluene; 7.22 mL, 13.0 mmol) was slowly added,
and the reaction mixture was stirred for 30 min at 0 °C. A solution
of epoxide 9a (1.62 g, 3.26 mmol) in benzene (30 mL) was added
to the DAHPA solution at once. The reaction mixture was warmed
to r.t., stirred for 3 h and then poured into sat. aq NH4Cl solution
(300 mL). The layers were separated and the aqueous layer was ex-
tracted with Et2O (2 × 300 mL). The combined organic layers were
washed with H2O and brine, dried over Na2SO4, and concentrated.
The residue was purified by flash chromatography (P–
EtOAc, 90:10) to yield the allylic alcohol 10a as a colorless liquid
(1.44 g, 2.90 mmol, 89%); Rf 0.07 (P–EtOAc, 95:5); [ ]D20 +37.0
(c 0.21, CH2Cl2).
as a colorless oil (3.85 g, 14.93 mmol, 68%); Rf 0.31 (P–
20
EtOAc, 80:20); [ ]D +9.6 (c 0.98, CHCl3).
IR (neat): 3444 (vs, br), 2928, 2856 (vs), 1471 (s), 1444 (m), 1362
(s), 1257 (vs), 1096 (vs), 1047 (vs), 895 (s), 836 (vs), 777 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 258 (2) [M+], 201 (6) [M+ – t-Bu], 183
(74), 131 (10), 109 (15), 81 (29), 75 (100), 59 (8), 43 (50).
Anal. Calcd for C13H26O3Si (258.165): C, 60.42; H, 10.14. Found:
C, 60.13; H, 10.01.
(1R,2R,4R,6S)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldi-
phenylsilyloxy)-1-methyl-7-oxabicyclo[4.1.0]heptane (9a)
A solution of 8a (1.0 g, 3.9 mmol), TBDPSCl (1.1 mL, 1.18 g, 4.3
mmol), and imidazole (394 mg, 5.8 mmol) in DMF (5 mL) was
stirred at 20 °C for 3 h. Et2O (60 mL) was added and the solution
was washed with H2O (60 mL). The aqueous layer was extracted
with Et2O (2 × 50 mL). The combined organic phases were washed
with H2O (100 mL) and brine (100 mL), dried (Na2SO4), filtered,
and the solvent was evaporated. Flash chromatography (P–
EtOAc, 98:2) gave 1.72 g (3.47 mmol, 88%) of the protected alco-
hol 9a as a colorless oil; Rf 0.36 (P–EtOAc, 95:5); [ ]D20 +33.8
(c 0.13, CHCl3).
IR (neat): 3342 (vs, br), 3071 (m), 2930, 2857 (vs), 1471 (m), 1428
(s), 1379 (m), 1257 (s), 1082 (vs), 885 (s), 832 (vs), 777 (s), 702
cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 481 (0.1) [M+ – CH3], 439 (9) [M+– t-
Bu], 361 (9), 307 (68), 263 (18), 253 (9), 197 (100), 183 (38), 157
(65), 73 (75).
Anal. Calcd for C29H44O3Si2 (496.283): C, 70.11; H, 8.93. Found:
C, 70.00; H, 8.92.
IR (neat): 3070 (w), 2930, 2857 (vs), 1472 (m), 1427 (m), 1374 (m),
1253 (s), 1112 (vs), 1073 (vs), 891 (s), 871 (s), 836 cm–1 (s).
MS (EI, 70 eV): m/z (%) = 496 (0.5) [M+], 439 (52) [M+ – t-Bu],
(1R,3R,5R)-3-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
nylsilyloxy)-2-methylenecyclohexanol (10b)
According to the preparation of 10a, a solution of compound 9b
(10.0 g, 20.2 mmol) in benzene (200 mL) was treated with DAHPA
(100 mmol) for 3 h at r.t. Flash chromatography (P–EtOAc, 90:10)
yielded the allylic alcohol 10b as a colorless liquid (9.92 g, 20.0
mmol, 99%); Rf 0.30 (P–EtOAc, 90:10); [ ]D20 –1.6 (c 0.87,
CHCl3).
361 (60), 253 (90), 223 (58), 183 (100), 157 (77), 135 (72), 73 (90).
Anal. Calcd for C29H44O3Si2 (496.283): C, 70.11; H, 8.93. Found:
C, 69.70; H, 8.98.
(1S,2R,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldi-
phenylsilyloxy)-1-methyl-7-oxabicyclo[4.1.0]heptane (9b)
The same procedure as for the preparation of 9a was used, starting
with 8b (2.91 g, 11.3 mmol). Yield: 5.27 g (10.6 mmol, 94%) of the
title compound 9b as a colorless oil; Rf 0.39 (P–EtOAc,= 95:5);
[ ]D20 +5.5 (c 0.75, CHCl3).
IR (neat): 3559 (vs, br), 3070 (m), 2929, 2856 (vs), 1472 (m), 1428
(s), 1373 (m), 1252 (s), 1112 (vs), 1078 (vs), 885 (s), 833 (vs), 775
(s), 701 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 481 (0.3) [M+ – CH3], 439 (16) [M+ – t-
Bu], 313 (74), 271 (32), 253 (28), 209 (67), 195 (68), 169 (100), 135
(40), 109 (50), 91 (38), 73 (45).
IR (neat): 3028 (w), 2930, 2857 (vs), 1472 (m), 1427 (m), 1373 (w),
1258 (s), 1112 (vs), 1078 (vs), 1032 (m), 896 cm–1 (m).
MS (EI, 70 eV): m/z (%) = 481 (0.5) [M+ – CH3], 439 (50) [M+– t-
Bu], 313 (38), 271 (62), 209 (100), 193 (65), 135 (32), 109 (48), 73
(47), 43 (51).
Anal. Calcd for C29H44O3Si2 (496.283): C, 70.11; H, 8.93. Found:
C, 70.16; H, 8.83.
(1R,3S,5R)-3-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphen-
ylsilyloxy)-2-methylenecyclohexanol (10c)
Anal. Calcd for C29H44O3Si2 (496.283): C, 70.11; H, 8.93. Found:
C, 69.93; H, 8.96.
According to the preparation of 10a, a solution of compound 9c
(30.6 g, 62 mmol) in benzene (400 mL) was treated with DAHPA
(240 mmol) for 5 h at r.t. Flash chromatography (P–EtOAc, 90:10)
yielded the allylic alcohol 10b as a colorless liquid (30.1 g, 60.7
mmol, 98%); Rf 0.23 (P–EtOAc, 90:10); [ ]D20 –11.2 (c 2.73,
CHCl3).
(1S,2S,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldi-
phenylsilyloxy)-1-methyl-7-oxabicyclo[4.1.0]heptane (9c)
The same procedure as for the preparation of 9a was used, starting
with 8c1a (16.0 g, 62 mmol). Yield: 30.6 g (62 mmol, quant.) of the
title compound 9c as a colorless oil (> 90% purity), which was used
in the following step without further purification; Rf 0.52 (P–
EtOAc, 90:10).
IR (neat): 3558 (vs, br), 3070 (s), 2961, 2891, 2859 (vs), 1472 (s),
1428 (s), 1389 (m), 1361 (s), 1252 (s), 1112 (vs), 904 (s), 825 (vs),
777 (s), 740 (s), 700 cm–1 (s).
1H NMR (360 MHz, CDCl3): = 0.03 (s, 3 H), 0.07 (s, 3 H), 0.87
(s, 9 H), 1.03 (s, 9 H), 1.22–1.46 (m, 5 H), 1.59–1.81 (m, 2 H), 2.99
(d, J = 4.5 Hz, 1 H), 4.03 (br s, 1 H), 4.46 (dd, J = 10.2 Hz, J = 5.4
Hz, 1 H), 7.34–7.59 (m, 6 H), 7.60–7.71 (m, 4 H).
13C NMR (90.6 MHz, CDCl3): = –4.7 (q), –4.2 (q), 18.0 (s), 19.1
(s), 20.0 (q), 25.7 (q), 26.9 (q), 32.8 (t), 35.7 (t), 59.2 (d), 60.0 (s),
67.6 (d), 68.7 (d), 127.5, 127.6, 129.6, 129.7 (d), 133.7, 134.1 (s),
135.7, 135.8 (d).
MS (EI, 70 eV): m/z (%) = 439 (18) [M+ – t-Bu], 361 (9), 199 (100),
183 (20), 157 (28), 73 (22).
Anal. Calcd for C29H44O3Si2 (496.283): C, 70.11; H, 8.93. Found:
C, 70.20; H, 9.07.
(1R,3S,5R)-1-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphen-
ylsilyloxy)-3-trimethylsilyloxy-2-methylenecyclohexane (1a)
A solution of 10a (1.31 g, 2.64 mmol), TMSCl (0.38 mL, 326 mg,
3 mmol), and imidazole (266 mg, 3.9 mmol) in DMF (5 mL) was
stirred at 20 °C for 4 h. Et2O (60 mL) was added and the solution
was washed with H2O (60 mL). The aqueous layer was extracted
with Et2O (2 × 50 mL). The combined organic layers were washed
with H2O (100 mL) and brine (100 mL), dried (Na2SO4), filtered,
(1S,3R,5R)-3-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
nylsilyloxy)-2-methylenecyclohexanol (10a)
A solution of N-cyclohexyl-N-iso-propylamine (2.18 mL, 1.79 g, 13
mmol) in benzene (50 mL) was cooled to 0 °C and a solution of n-
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

PAPER
Cyclohexane-1,3,5-triols
1833
and the solvent was evaporated. Flash chromatography (P–
EtOAc, 99:1) gave 1.49 g (2.64 mmol, quant.) of the title compound
1a as a colorless oil; Rf 0.45 (P–EtOAc, 95:5); [ ]D20 +10.5 (c 0.20,
CHCl3).
(2R,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphen-
ylsilyloxy)-6-trimethylsilyloxy-cyclohexanone (2b)
The ozonolysis was carried out as described for the preparation of
2b with a solution of 1b (6.2 g, 10.9 mmol) in a mixture of Et3N (3
mL), MeOH (60 mL), and CH2Cl2 (300 mL) until a blue color per-
sisted. Purification by flash chromatography (P–EtOAc, 98:2)
yielded the desired product 2b as a colorless oil (6.2 g, 10.9 mmol,
quant.); Rf 0.53 (P–EtOAc, 90:10); [ ]D20 –1.5 (c 0.86, CHCl3).
IR (neat): 3072 (m), 2955, 2857 (vs), 1471 (m), 1424 (m), 1251 (s),
1088 (s), 837 cm–1 (m).
MS (EI, 70 eV): m/z (%) = 553 (3) [M+ – CH3], 511 (15) [M+ –
t-Bu], 255 (18), 229 (33), 197 (100), 181 (14), 155 (86), 73 (82).
IR (neat): 3069 (m), 2954, 2857 (vs), 1743 (vs), 1472 (m), 1428 (m),
1361 (w), 1254 (s), 1095 (vs), 1051 (m), 919 (m), 838 (vs), 702
cm–1 (s).
Anal. Calcd for C32H52O3Si3 (568.322): C, 67.55; H, 9.21. Found:
C, 67.42; H, 9.24.
MS (EI, 70 eV): m/z (%) = 555 (4) [M+ – CH3], 513 (60) [M+ –
t-Bu], 423 (22), 397 (19), 253 (28), 195 (28), 135 (48), 73 (100).
(1R,3R,5R)-1-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
nylsilyloxy)-3-trimethylsilyloxy-2-methylenecyclohexane (1b)
The same procedure as for the preparation of 1a was used, starting
with 10b (9.22 g, 18.6 mmol). Yield: 10.5 g (18.5 mmol, quant.) of
the title compound 1b as a colorless oil; Rf 0.78 (P–EtOAc, 98:2);
[ ]D20 –13.5 (c 0.88, CHCl3).
Anal. Calcd for C31H50O4Si3 (570.302): C, 65.21; H, 8.83. Found:
C, 64.99; H, 8.89.
(2S,4R,6R)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphen-
ylsilyloxy)-6-trimethylsilyloxy-cyclohexanone (2c)
IR (neat): 3071 (m), 2955, 2857 (vs), 1472 (m), 1428 (m), 1251 (s),
1088 (s), 838 cm–1 (m).
MS (EI, 70 eV): m/z (%) = 553 (4) [M+ – CH3], 511 (8) [M+ – t-Bu],
The ozonolysis was carried out as described for the preparation of
2a with a solution of 1c (12.1 g, 21.3 mmol) in a mixture of Et3N (3
mL), MeOH (60 mL), and CH2Cl2 (300 mL) until a blue color per-
sisted. Purification by flash chromatography (P–EtOAc, 95:5)
yielded the desired product 2c as a colorless oil (11.6 g, 20.3 mmol,
95%); Rf 0.54 (P–EtOAc, 80:20); [ ]D20 –1.6 (c 1.23, CHCl3).
395 (6), 195 (9), 181 (20), 155 (100), 73 (40).
Anal. Calcd for C32H52O3Si3 (568.322): C, 67.55; H, 9.21. Found:
C, 67.55; H, 9.26.
IR (neat): 3071 (m), 2957, 2857 (vs), 1745 (vs), 1471 (s), 1428 (s),
1361 (m), 1250 (vs), 1164 (s), 1112 (vs), 1076 (vs), 1034 (vs), 952
(s), 917 (s), 838 (vs), 702 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 555 (5) [M+ – CH3], 513 (48) [M+ –
t-Bu], 423 (50), 397 (40), 355 (22), 257 (100), 197 (27, 135 (55), 73
(80).
(1S,3R,5R)-1-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphen-
ylsilyloxy)-3-trimethylsilyloxy-2-methylenecyclohexane (1c)
The same procedure as for the preparation of 1a was used, starting
with 10c (16.0 g, 32.2 mmol): yield 13.4 g (23.5 mmol, 73%) of the
title compound 1c as a colorless oil; Rf 0.69 (P–EtOAc, 90:10);
[ ]D20 –3.3 (c 2.73, CHCl3).
Anal. Calcd for C31H50O4Si3 (570.302): C, 65.21; H, 8.83. Found:
C, 65.15; H, 8.54.
IR (neat): 3071 (m), 2956, 2857 (vs), 1472 (m), 1428 (m), 1251 (vs),
1105 (vs), 1071 (vs), 922 (s), 889 (vs), 838 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 553 (6) [M+ – CH3], 511 (80) [M+ –
t-Bu], 395 (35), 353 (30), 255 (48), 229 (45), 199 (32), 181 (15), 73
(100).
(1S,2R,4R,6S)-1-Allyl-2-(tert-butyldimethylsilanyl-oxy)-4-(tert-
butyldiphenylsilyloxy)-6-trimethyl-silyloxycyclohexanol (12a)
A stirred solution of 2a (330 mg, 0.57 mmol) in THF (20 mL) was
cooled to –78 °C and allylmagnesium chloride (1 M in Et2O; 1.0
mL, 1.0 mmol) was added dropwise. The clear, yellow solution was
stirred for 1 h at –78 °C. The reaction was quenched by the addition
of sat. aq NH4Cl solution (150 mL), and allowed to warm to ambient
temperature. The mixture was diluted with Et2O (150 mL). After
separation, the aqueous layer was extracted with Et2O (2 × 100
mL). The organic extracts were combined, washed with H2O (200
mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated
to dryness on a rotatory evaporator to give 320 mg of crude product
as a pale yellow oil (dr 3:1, determined by 1H NMR). The residue
was chromatographed (P–EtOAc, 90:10) to yield 12a and its epimer
as mixture of diastereoisomers (262 mg, 0.43 mmol, 75%; dr 3:1,
determined by 1H NMR). The pure title compound was obtained by
flash chromatography (P–EtOAc, 98:2) to give 12a (196 mg, 0.32
mmol, 56%) as a colorless oil; Rf 0.28 (P–EtOAc, 95:5);
[ ]D20 +12.6 (c 1.08, CHCl3).
Anal. Calcd for C32H52O3Si3 (568.322): C, 67.55; H, 9.21. Found:
C, 67.49; H, 9.22.
(2R,4R,6S)-2-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphen-
ylsilyloxy)-6-trimethylsilyloxy-cyclohexanone (2a)
A solution containing alkene 1a (1.39 g, 2.44 mmol), Et3N (0.3
mL), MeOH (6 mL) and CH2Cl2 (30 mL) was cooled to –78 °C.
Ozonized oxygen gas was passed through the solution until a blue
color persisted. While still at –78 °C, the reaction mixture was
flushed with N2 for 30 min (after 15 min the blue color had disap-
peared) and Me2S (1.34 mL, 1.12 g, 18 mmol) was added. The mix-
ture was stirred for an additional 30 min at this temperature and was
then allowed to warm to r.t. over 2 h and then treated with aq
NaHCO3 (300 mL of a 1% solution). After separation the aqueous
layer was extracted with CH2Cl2 (100 mL) and the combined organ-
ic layers were washed with brine (100 mL), dried (Na2SO4), filtered
and concentrated in vacuo. Purification by flash chromatography
(P–EtOAc, 98:2) yielded the desired product 2a as a colorless oil
(1.18 g, 2.07 mmol, 85%); Rf 0.35 (P–EtOAc, 95:5); [ ]D20 +7.3
(c 0.95, CH2Cl2).
IR (neat): 3571 (m, sh), 3072 (m), 2954, 2858 (s), 1472 (s), 1428 (s),
1389 (m), 1252 (s), 1084 (s, br), 1005 (m), 911 (s), 838 (s), 776 (m),
740 cm–1 (m).
1H NMR (360 MHz, CDCl3): = –0.04 (s, 3 H), –0.03 (s, 3 H), 0.03
(s, 9 H), 0.88 (s, 9 H), 1.07 (s, 9 H), 1.70-1.83 (m, 2 H), 1.82-1.99
(m, 2 H), 2.14 (s, 1 H, OH), 2.36 (dd, J = 13.6 Hz, J = 7.0 Hz, 1 H),
2.47 (dd, J = 13.6 Hz, J = 8.0 Hz, 1 H), 3.24 (dd, J = 11.8 Hz,
J = 4.3 Hz, 1 H), 3.29 (dd, J = 11.1 Hz, J = 5.0 Hz, 1 H), 3.98 (tt,
J = 11.1 Hz, J = 4.5 Hz, 1 H), 4.98-5.09 (m, 2 H), 5.55-5.67 (m, 1
H), 7.35–7.40 (m, 6 H), 7.63–7.69 (m, 4 H).
IR (neat): 3071 (m), 2954, 2857 (vs), 1750 (vs), 1471 (m), 1428 (m),
1389 (m), 1361 (w), 1251 (s), 1153 (s), 1087 (vs), 1001 (vs), 938
(m), 888 (s), 838 cm–1 (vs).
MS (EI, 70 eV): m/z (%) = 555 (5) [M+ – CH3], 513 (38) [M+ –
t-Bu], 423 (50), 257 (80), 197 (30), 135 (64), 73 (100).
Anal. Calcd for C31H50O4Si3 (570.302): C, 65.21; H, 8.83. Found:
C, 64.77; H, 8.90.
13C NMR (90.6 MHz, CDCl3): = –4.9 (q), –3.8 (q), 0.5 (q), 18.1
(s), 19.0 (s), 25.9 (q), 26.9 (q), 38.6 (t), 38.9 (t), 39.4 (t), 66.1 (d),
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

1834
S. Kirsch, T. Bach
PAPER
69.3 (d), 69.4 (d), 75.2 (s), 117.9 (t), 127.6 (d), 127.6 (d), 129.6 (d),
129.6 (d), 133.6 (d), 134.3 (s), 134.3 (s), 135.7 (d), 135.7 (d).
MS (EI, 70 eV): m/z (%) = 612 (1) [M+], 555 (11) [M+ – t-Bu], 477
3.76–3.89 (m, 2 H), 5.02 (dd, J = 10.2 Hz, J = 2.3 Hz, 1 H), 5.06–
5.13 (m, 3 H), 5.54–5.65 (m, 1 H), 7.37–7.40 (m, 6 H), 7.60–7.69
(m, 4 H).
13C NMR (90.6 MHz, CDCl3): = –4.9 (q), –3.8 (q), 0.5 (q), 17.9
(s), 19.0 (s), 25.9 (q), 26.9 (q), 33.0 (t), 38.9 (t), 39.1 (t), 58.9 (q),
65.8 (t), 66.4 (d), 69.9 (d), 69.9 (d), 71.9 (t), 79.8 (s, C1), 90.6 (t),
118.2 (t), 127.6 (d), 127.6 (d), 129.6 (d), 129.6 (d), 133.5 (d), 134.3
(s), 134.3 (s), 135.7 (d).
(28), 361 (32), 299 (38), 229 (30), 209 (54), 135 (53), 73 (100).
Anal. Calcd for C34H56O4Si3 (612.349): C, 66.61; H, 9.21. Found:
C, 66.48; H, 9.32.
(1S,2R,4R,6R)-1-Allyl-2-(tert-butyldimethylsilyloxy)-4-(tert-bu-
tyldiphenylsilyloxy)-6-trimethyl-silyloxycyclohexanol (12b)
A stirred solution of 2b (5.0 g, 8.8 mmol) in THF (150 mL) was
cooled to –20 °C and allylmagnesium chloride (1 M in Et2O; 13.2
mL, 13.2 mmol) was added dropwise. The clear solution was stirred
for 1 h at –78 °C. The reaction was quenched by the addition of sat.
aq NH4Cl solution (300 mL), and allowed to warm to ambient tem-
perature. The mixture was diluted with Et2O (300 mL). After sepa-
ration, the aqueous layer was extracted with Et2O (2 × 200 mL). The
organic extracts were combined, washed with H2O (400 mL) and
brine (300 mL), dried (Na2SO4), filtered, and concentrated to give
the crude product (dr 9:1, determined by 1H NMR) as a yellow oil.
The residue was purified by flash chromatography (P–EtOAc, 98:2)
to yield 12b and its epimer as unseparable mixture of diastereoiso-
mers (5.4 g, 8.8 mmol, quant.; dr 9:1, determined by 1H NMR); Rf
0.65 (P–EtOAc, 90:10); [ ]D20 –10.5 (c 0.94, CHCl3).
MS (EI, 70 eV): m/z (%) = 443 (1) [M+ – t-Bu], 369 (15), 339 (30),
257 (64), 133 (100), 89 (50), 59 (30) [CH3OCH2CH2 ].
+
Anal. Calcd for C38H64O6Si3 (700.401): C, 65.09; H, 9.20. Found:
C, 65.18; H, 9.24.
(1S,2R,4R,6R)-1-Allyl-1-(2-methoxyethoxymethoxy)-2-(tert-bu-
tyldimethylsilyloxy)-4-(tert-butyldiphenylsilyloxy)-6-trimethyl-
silyloxycyclohexane (13b)
A solution of tertiary alcohol 12b (5.4 g, 8.8 mmol) in 1,2-dichloro-
ethane (40 mL) was treated with i-Pr2NEt (2.3 mL, 1.7 g, 13.2
mmol) and MEMCl (1.0 mL, 1.0 g, 8.8 mmol) at 0 °C. After stirring
for 4 h at 70 °C, i-Pr2NEt (2.3 mL, 1.7 g, 13.2 mmol) and MEMCl
(1.0 mL, 1.0 g, 8.8 mmol) were added to the orange-colored solu-
tion. The reaction mixture was stirred for additional 4 h at 70 °C,
cooled to r.t., and diluted with CH2Cl2 (100 mL) and sat. aq NH4Cl
solution (100 mL). The aqueous layer was extracted with CH2Cl2
(100 mL), the combined organic layers were washed with H2O (100
mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated.
Purification by flash chromatography (P–EtOAc, 98:2) gave 13b
(4.9 g, 7.0 mmol, 80%) as a yellow oil; Rf 0.47 (P–EtOAc, 90:10);
[ ]D20 –6.8 (c 1.10, CHCl3).
IR (neat): 3572 (m, sh), 3072 (m), 2954, 2856 (s), 1471 (s), 1428 (s),
1379 (m), 1361 (m), 1251 (s), 1068 (s, br), 941 (s), 838 (s), 776
cm–1 (s).
1H NMR (360 MHz. CDCl3): = –0.11 (s, 3 H), –0.06 (s, 12 H),
0.85 (s, 9 H), 1.05 (s, 9 H), 1.63–1.78 (m, 2 H), 1.83 (virt d, J = ca.
13.1 Hz, 1 H), 1.97 (virt dt, J = ca. 1.9 Hz, J = ca. 13.1 Hz, 1 H),
2.06 (s, 1 H, OH), 2.21 (dd, J = 14.2 Hz, J = 8.0 Hz, 1 H), 2.38 (dd,
J = 14.2 Hz, J = 6.2 Hz, 1 H), 3.49 (dd, J = 10.7 Hz, J = 5.4 Hz, 1
H), 3.86 (virt. s, 1 H), 3.98 (virt. sept, J = ca. 6.0 Hz 1 H), 5.02–5.09
(m, 2 H), 5.84–5.95 (m, 1 H), 7.34–7.40 (m, 6 H), 7.63–7.69 (m, 4
H).
13C NMR (90.6 MHz, CDCl3): = –5.0 (q), –4.2 (q), 0.28 (q), 17.9
(s), 19.1 (s), 25.8 (q), 26.9 (q), 37.7 (t), 39.2 (t), 40.1 (t), 65.8 (d),
70.9 (d), 71.0 (d), 74.0 (s), 117.6 (t), 127.5 (d), 127.5 (d), 129.5 (d),
129.6 (d), 134.2 (s), 134.3 (s), 134.6 (d), 135.8 (d).
IR (neat): 3072 (m), 2955, 2893, 2857 (s), 1472 (s), 1427 (s), 1379
(m), 1361 (m), 1251 (vs), 1112 (vs), 1070 (vs, br), 1024 (vs), 914
(s), 838 cm–1 (s).
1H NMR (500 MHz, CDCl3): = –0.15 (s, 3 H), –0.08 (s, 3 H),
–0.07 (s, 9 H), 0.84 (s, 9 H), 1.06 (s, 9 H), 1.73 (virt. dt, J = ca. 11.8
Hz, J = 4.6 Hz, 1 H), 1.75–1.86 (m, 2 H), 2.04 (virt. dt, J = ca. 2.2
Hz, J = 11.1 Hz, 1 H), 2.13 (dd, J = 15.5 Hz, J = 7.9 Hz, 1 H), 2.80
(dd, J = 15.5 Hz, J = 6.0 Hz, 1 H), 3.44 (s, 3 H), 3.52 (dd, J = 12.0
Hz, J = 4.6 Hz, 1 H), 3.62 (t, J = 5.4 Hz, 2 H), 3.74–3.86 (m, 3 H),
3.97 (virt. sept, J = ca. 4.6 Hz, 1 H), 5.03–5.13 (m, 4 H), 5.86–5.95
(m, 1 H), 7.34–7.40 (m, 6 H), 7.61–7.69 (m, 4 H).
13C NMR (90.6 MHz, CDCl3): = –5.3 (q), –4.6 (q), 0.27 (q), 17.8
(s), 19.1 (s), 25.7 (q), 26.9 (q), 32.7 (t), 37.5 (t), 40.1 (t), 59.0 (q),
66.6 (d), 67.6 (t), 71.1 (d, C2), 71.6 (d, C4), 71.8 (t), 78.9 (s, C1),
90.8 (t), 117.5 (t), 127.4 (d), 127.5 (d), 129.4 (d), 129.5 (d), 133.6
(d), 134.3 (s), 134.7 (s), 135.7 (d).
MS (EI, 70 eV): m/z (%) = 571 (5) [M+ – C3H5], 465 (50), 339 (52),
209 (48), 135 (65), 73 (100).
Anal. Calcd for C34H56O4Si3 (612.349): C, 66.61; H, 9.21. Found:
C, 66.27; H, 9.17.
(1S,2R,4R,6S)-1-Allyl-1-(2-methoxyethoxymethoxy)-2-(tert-bu-
tyldimethylsilyloxy)-4-(tert-butyldiphenylsilyloxy)-6-trimethyl-
silyloxycyclohexane (13a)
MS (EI, 70 eV): m/z (%) = 443 (6) [M+ – t-Bu], 553 (5), 463 (9),
A solution of tertiary alcohol 12a (180 mg, 0.29 mmol) in 1,2-
dichloroethane (7 mL) was treated with i-Pr2NEt (0.34 mL, 259 mg,
2 mmol) and MEMCl (0.15 mL, 162 mg, 1.3 mmol) at 0 °C. The or-
ange-colored solution was stirred for 4 h at 70 °C, cooled to r.t., di-
luted with CH2Cl2 (50 mL) and sat. aq NH4Cl solution (50 mL). The
aqueous layer was extracted with CH2Cl2 (50 mL), the combined or-
ganic layers were washed with H2O (50 mL) and brine (50 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash chromatography (P–EtOAc, 98:2) gave 13a (162 mg, 0.23
mmol, 79%) as a yellow oil; Rf 0.20 (P–EtOAc, 95:5); [ ]D20 –43.4
(c 0.17, CH2Cl2).
369 (20), 339 (30), 257 (64), 213 (18), 133 (100), 89 (54), 59 (48)
[CH3OCH2CH2 ].
+
Anal. Calcd for C38H64O6Si3 (700.401): C, 65.09; H, 9.20. Found:
C, 65.13; H, 9.21.
(1S,2S,3R,5R)-2-Allyl-3-(tert-butyldimethylsilyloxy)-5-(tert-bu-
tyldiphenylsilyloxy)-2-(2-methoxyethoxymethoxy)cyclohex-
anol (14a)
To a solution of 13a (120 mg, 0.17 mmol) in MeOH (10 mL) was
added K2CO3 (300 mg) at 0 °C. The mixture was allowed to warm
to r.t. After 8 h, sat. aq NH4Cl solution (100 mL) and CH2Cl2 (100
mL) were added. The aqueous layer was separated and extracted
with CH2Cl2 (50 mL). The organic extracts were combined, washed
with H2O (100 mL) and brine (100 mL), dried over Na2SO4, filtered
and concentrated. The crude product was purified by flash chroma-
tography (P–EtOAc, 85:15) to give 105 mg (0.17 mmol, quant.) of
14a as a colorless oil; Rf 0.16 (P–EtOAc, 90:20); [ ]D20 –29.2
(c 0.37, CHCl3).
IR (neat): 3072 (m), 2952, 2857 (s), 1471 (s), 1427 (s), 1250 (vs),
1112 (vs), 1072 (vs), 1024 (vs), 914 (s), 838 cm–1 (s).
1H NMR (360 MHz, CDCl3): = –0.07 (s, 3 H), –0.06 (s, 3 H),
–0.01 (s, 9 H), 0.86 (s, 9 H), 1.07 (s, 9 H), 1.65–1.79 (m, 2 H), 1.96
(virt. q, J = ca.11.6 Hz, 2 H), 2.74 (virt. d, J = ca. 7.3 Hz, 2 H), 3.23
(dd, J = 11.4 Hz, J = 4.1 Hz, 1 H), 3.27 (dd, J = 11.4 Hz, J = 4.1 Hz,
1 H), 3.42 (s, 3 H), 3.48–3.57 (m, 1 H), 3.56 (t, J = 4.8 Hz, 2 H),
Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

PAPER
Cyclohexane-1,3,5-triols
1835
IR (neat): 3478 (m, br), 3071 (m), 2955, 2930, 2892, 2857 (s), 1472
(s), 1427 (m), 1374 (m), 1361 (m), 1251 (s), 1111 (vs), 1061 (vs,
br), 1025 (vs), 835 (s), 702 cm–1 (s).
Et2O (300 mL) and sat. aq NaHCO3 solution (300 mL). The layers
were separated, the aqueous layer was extracted with Et2O (150
mL). The combined organic layers were washed with H2O (2 × 400
mL), dried over Na2SO4, filtered, and concentrated. Flash chroma-
tography (P–EtOAc, 95:5) of the crude oil gave gave the title com-
pound (11) (4.0 g, 6.4 mmol, 98%) as a colorless oil; Rf 0.34 (P–
EtOAc, 90:10); [ ]D20 –10.1 (c 0.98, CHCl3).
1H NMR (360 MHz, CDCl3): = –0.14 (s, 3 H), –0.11 (s, 3 H), 0.84
(s, 9 H), 1.06 (s, 9 H), 1.63–1.72 (m, 1 H), 1.80 (virt. q, J = ca..6 Hz,
1 H), 1.86 (virt. q, J = ca. 11.6 Hz, 1 H), 1.97–2.05 (m, 1 H), 2.63
(dd, J = 12.7 Hz, J = 7.8 Hz, 1 H), 2.70 (dd, J = 12.7 Hz, J = 7.0
Hz, 1 H), 2.97 (br s, 1 H, OH), 3.17-3.27 (m, 2 H), 3.42 (s, 3 H),
3.50–3.62 (m, 3 H), 3.72–3.78 (m, 1 H), 3.83–3.89 (m, 1 H), 4.83
(d, J = 7.2 Hz, 1 H), 5.05 (dd, J = 10.1 Hz, J = 2.2 Hz, 1 H), 5.18
(dd, J = 17.0 Hz, J = 2.2 Hz, 1 H), 5.19 (d, J = 7.2 Hz, 1 H), 5.60–
5.73 (m, 1 H), 7.33–7.44 (m, 6 H), 7.60–7.70 (m, 4 H).
13C NMR (90.6 MHz): = –5.1 (q), –3.9 (q), 17.9 (s), 19.1 (s), 25.8
(q), 26.9 (q), 32.8 (t), 39.2 (t), 39.3 (t), 58.9 (q), 66.3 (d), 67.8 (t),
70.1 (d), 72.0 (t), 80.7 (s), 90.9 (t), 118.9 (t), 127.6 (d), 127.6 (d),
129.6 (d), 129.6 (d), 133.1 (d), 134.1 (s), 134.4 (s), 135.6 (d), 135.7
(d).
The same procedure above was used, starting with 14a (30 mg,
4.7 × 10–2 mmol) and IBX17 (28 mg, 0.1 mmol) in DMSO (1 mL).
Yield: 26 mg (0.041 mmol, 88%) of the title compound 11 as a col-
orless oil; Rf 0.34 (P–EtOAc, 90:10); [ ]D20 –9.9 (c 0.51, CHCl3).
IR (neat): 3072 (m), 2931, 2857 (s), 1721 (s), 1472 (s), 1427 (s),
1377 (m), 1255 (s), 1113 (vs), 1021 (vs), 837 (s), 703 cm–1 (s).
1H NMR (500 MHz, CDCl3): = –0.12 (s, 3 H), –0.10 (s, 3 H), 0.85
(s, 9 H), 1.07 (s, 9 H), 1.86 (ddt, J = 11.9 Hz, J = 1.7 Hz, J = 4.4 Hz,
1 H), 2.30 (virt. q, J = ca. 11.9 Hz, 1 H), 2.49 (dd, J = 14.2 Hz,
J = 7.3 Hz, 1 H), 2.52 (ddd, J = 12.8 Hz, J = 5.2 Hz, J = 1.7 Hz, 1
H), 2.77 (dd, J = 14.2 Hz, J = 6.6 Hz, 1 H), 3.17 (dd, J = 12.8 Hz,
J = 11.2 Hz, 1 H), 3.29 (dd, J = 11.9 Hz, J = 4.4 Hz, 1 H), 3.41 (s,
3 H), 3.57 (t, J = 4.6 Hz, 2 H), 3.69 (virt. sept, J = ca. 4.9 Hz, 1 H),
3.72–3.82 (m, 2 H), 4.92 (d, J = 6.3 Hz, 1 H), 4.94 (d, J = 6.3 Hz,
1 H), 5.03 (dd, J = 10.2 Hz, J = 1.9 Hz, 1 H), 5.12 (dd, J = 17.3 Hz,
J = 1.9 Hz, 1 H), 5.64–5.73 (m, 1 H), 7.33–7.42 (m, 6 H), 7.59–7.68
(m, 4 H).
13C NMR (90.6 MHz, CDCl3): = –4.9 (q), –4.0 (q), 17.9 (s), 19.0
(s), 25.8 (q), 26.9 (q), 32.8 (t), 39.1 (t), 47.5 (t), 58.9 (q), 65.9 (d),
67.7 (t), 71.1 (d), 71.7 (t), 83.9 (s), 91.3 (t), 118.2 (t), 127.7 (d),
127.7 (d), 129.8 (d), 129.8 (d), 133.4 (d), 133.5 (s), 133.8 (s), 135.6
(d), 135.7 (d), 205.7 (s).
MS (EI, 70 eV): m/z (%) = 587 (0.3) [M+ – C3H5], 553 (6), 495 (28),
465 (10), 363 (32), 257 (85),135 (45), 89 (72), 59 (100)
+
[CH3OCH2CH2 ].
Anal. Calcd for C35H56O6Si2 (628.362): C, 66.83; H, 8.97. Found:
C, 66.77; H, 8.94.
(1R,2S,3R,5R)-2-Allyl-3-(tert-butyldimethylsilanyl-oxy)-5-(tert-
butyldiphenylsilyloxy)-2-(2-methoxyethoxymethoxy) cyclohex-
anol (14b)
To a solution of 13b (4.9 g, 7.0 mmol) in MeOH (60 mL) was added
K2CO3 (1.8 g) at 0 °C. The mixture was allowed to warm to r.t. Af-
ter 12 h sat. aq NH4Cl solution (400 mL) and CH2Cl2 (400 mL) were
added. The aqueous layer was separated and extracted with CH2Cl2
(300 mL). The organic extracts were combined, washed with H2O
(400 mL) and brine (400 mL), dried over Na2SO4, filtered and con-
centrated. The crude product was purified by flash chromatography
(P–EtOAc, 90:10) to give 4.2 g (6.7 mmol, 95%) of 14b as a color-
less oil; Rf 0.17 (P–EtOAc, 90:10); [ ]D20 +0.4 (c 2.02, CHCl3).
MS (EI, 70 eV): m/z (%) = 626 (1) [M+], 569 (5) [M+ – C(CH3)3],
493 (2), 370 (10), 281 (15), 257 (48), 199 (32), 133 (46), 89 (100),
+
59 (80) [CH3OCH2CH2 ].
Anal. Calcd for C35H54O6Si2 (626.346): C, 67.05; H, 8.68. Found:
C, 66.90; H, 8.73.
IR (neat): 3478 (m, br), 3071 (m), 2955, 2930, 2892, 2857 (s), 1472
(s), 1427 (m), 1374 (m), 1361 (m), 1251 (s), 1111 (vs), 1061 (vs,
br), 1025 (vs), 835 (s), 702 cm–1 (s).
Acknowledgment
Financial support by Bayer AG (Wuppertal) is gratefully acknow-
ledged. We thank Olaf Ackermann for excellent technical assi-
stance.
1H NMR (360 MHz, CDCl3): = –0.12 (s, 3 H), –0.07 (s, 3 H), 0.84
(s, 9 H), 1.07 (s, 9 H), 1.41 (br d, J = 4.3 Hz, 1 H, OH), 1.63–1.74
(m, 2 H), 1.80 (virt. q, J = ca. 11.4 Hz, 1 H), 1.96 (ddd, J = 14.8 Hz,
J = 11.4 Hz, J = 2.9 Hz, 1 H), 2.08 (dd, J = 15.5 Hz, J = 9.3 Hz, 1
H), 2.86 (dd, J = 15.5 Hz, J = 5.0 Hz, 1 H), 3.42 (s, 3 H), 3.51-3.58
(m, 3 H), 3.62–3.68 (m, 1 H), 3.71–3.75 (m, 1 H), 3.76–3.82 (m, 1
H), 3.99 (virt. sept, J = ca. 4.8 Hz, 1 H), 4.89 (d, J = 6.1 Hz, 1 H),
5.03–5.12 (m, 2 H), 5.18 (d, J = 6.1 Hz, 1 H), 5.93–6.09 (m, 1 H),
7.33–7.40 (m, 6 H), 7.61–7.71 (m, 4 H).
References
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Herdewijn, P. J. Org. Chem. 1998, 63, 3051. (b) Wang, J.;
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13C NMR (90.6 MHz, CDCl3): = –5.1 (q), –4.5 (q), 17.8 (s), 19.1
(s), 25.8 (q), 26.9 (q), 34.7 (t), 37.3 (t), 40.1 (t), 59.0 (q), 66.6 (d),
67.5 (t), 70.7 (d), 71.9 (t), 72.3 (d), 78.8 (s), 91.1 (t), 117.4 (t), 127.5
(d), 127.5 (d), 129.5 (d), 129.5 (d), 134.5 (d), 134.6 (s), 134.8 (s),
135.7 (d), 135.8 (d).
MS (EI, 70 eV): m/z (%) = 587 (1) [M+ – C3H5], 571 (5) [M+– t-Bu],
495 (8), 465 (10), 297 (18), 257 (100), 133 (68), 89 (52), 59 (58)
(5) Synthesis of Wailupemycin B: Kirsch, S.; Bach, T. Angew.
Chem. Int. Ed. 2003, 42, in print.
+
[CH3OCH2CH2 ].
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Anal. Calcd for C35H56O6Si2 (628.362): C, 66.83; H, 8.97. Found:
C, 66.78; H, 8.97.
(2R,3R,5S)-2-Allyl-3-(tert-butyldimethylsilyloxy)-5-(tert-butyl-
diphenylsilyloxy)-2-(2-methoxyethoxymethoxy)cyclohexanone
(11)
Alcohol 14b (4.1 g, 6.5 mmol) was dissolved in DMSO (30 mL),
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solution was stirred for 12 h at r.t., then poured into a mixture of
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Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York

1836
S. Kirsch, T. Bach
PAPER
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Synthesis 2003, No. 12, 1827–1836 © Thieme Stuttgart · New York